Project Summary/Abstract Statement of the problem: Only three pharmacotherapeutic treatments for Alcohol Use Disorder (AUD) are FDA approved and none are widely used (<10% of AUD patients) or show a strong effect to reduce risky- or dependence-based drinking in the long-term (<20% see sustained decreased drinking outcomes). Unfortunately, approximately 10% of the population suffers from AUD and over 5% of all medical morbidities share risky ethanol consumption as an underlying issue. As a consequence, intoxication, in general, and ?alcohol addiction? (severe AUD), in particular, are important clinical problems. Given the limited pharmacotherapeutic choice, there is a compelling need for continued development of new treatments across the AUD spectrum (mild to severe DSM- V classification). Our published and preliminary data indicated an efficacy of tetracycline analogs with C6?-H to reduce several important traits related to AUD, including decreases in binge drinking, chronic (dependence- related) consumption, physical withdrawal symptoms and ethanol-induced pain sensitization. However, a healthy microbiota has recently garnered much attention. Therefore, we designed seven new minocycline analogs that have no antimicrobial action and should not negatively affect GI function. Preliminary data demonstrated positive results in high consumption murine and porcine AUD models. In this STTR application, for Phase I, we propose preclinical studies to determine the potential to treat AUD for the seven chemically-modified tetracycline analogs (CMTs). Phase I will evaluate the hypothesis that our newly designed CMTs without antimicrobial properties will be effective in the reduction of binge and dependence drinking, consistent with translation for use in human treatment of mild to severe AUD (?alcohol abuse? and ?alcoholism?). We will identify a lead compound using the following aims: Aim 1: CMTs will be verified for loss of antibiotic activity and chemical structure using CFU assays and NMR and MS respectively. Aim 2: Development of lead compounds will be completed using drug screens for AUD traits in C57BL/6J mice. Analogs will be tested for efficacy to lower 1) ?binge? (acute) and 2) ?dependence? (chronic) consumption in AUD models, which importantly reach pharmacologically relevant blood alcohol levels. Aim 3: A dose-response relationship will be tested for two lead compounds using Aim 2 tests. Future Phase II plans include the testing of lead compounds in our novel swine model and pharmacokinetic studies to understand timing for best therapeutic value as well as potential for development of tolerance, followed by toxicology screens. Impact: The development of a drug without addiction potential that targets several aspects of AUD symptoms (drinking, withdrawal, associated pain) has critical advantages over current therapies.